Targeting Protein Kinases for Cancer Therapy

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  • Edition: 1st
  • Format: Hardcover
  • Copyright: 2010-02-15
  • Publisher: Wiley

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This book provides an overview of different protein kinases structure, function, regulation, and their role in cancer. It combines kinase biology with chemistry and pharmacology applications for discovery and development of cancer drugs. The text also describes existing and emerging kinase inhibitors, focusing mostly on small molecules but also alternative approaches like therapeutic antibodies. Provides an important resource that helps pharmaceutical researchers understand and work in this dynamic area of cancer drug research.

Author Biography

David J. Matthews is Executive Director of Oncology Discovery at Exelixis, where he is responsible for cancer drug discovery. For more than fifteen years. Dr. Matthews has been involved in drug discovery projects in industry, with particular focus on small molecule inhibitors. He has twenty scientific publications and multiple patents to his credit. Mary E. Gerritsen is Vice President of Molecular and Cellular Pharmacology at Exelixis, where she is in charge of cell-based screening in preclinical research and of biomarker studies for clinical development compounds in Phase I and II studies. Her prior industry experience includes positions at Genentech, Bayer, and Millennium Pharmaceuticals. She has authored more than one hundred peer-reviewed articles and twenty-six book chapters and is an inventor on forty-two issued patents.

Table of Contents

Prefacep. xi
Acknowledgmentsp. xiii
Kinases and Cancerp. 1
A Brief History of Protein Phosphorylationp. 1
Kinases and Cancerp. 3
A Tour of the Human Protein Kinase Superfamilyp. 8
Tyrosine Kinase Groupp. 12
TKL (Tyrosine Kinase-like) Groupp. 22
STE Groupp. 25
CSNK1 Groupp. 27
AGC Groupp. 28
CAMK Groupp. 30
CMGC Groupp. 32
RGC Groupp. 36
Othersp. 36
Atypical Protein Kinasesp. 41
Nonprotein Kinasesp. 41
Strategic Considerations for Selecting Kinases as Drug Targetsp. 46
Comparison of Kinase Inhibitor Therapeutic Strategiesp. 51
Small Molecule Versus Antibody-Directed Therapiesp. 51
Alternative Strategies for Kinase Inhibitionp. 51
Referencesp. 58
Protein Kinase Structure, Function and Regulationp. 75
Ligand Binding to Receptor Tyrosine Kinasesp. 76
EGF: EGF Receptor Interactionsp. 76
Insulin: Insulin Receptor and IGF1:IGF1Rp. 78
FGF: FGF Receptor (Heparin/Heparan Sulfate) Interactionsp. 79
VEGF: VEGF Receptor Interactionsp. 80
Angiopoietin2: TIE2 Receptor Interactionsp. 80
Ephrin: EPH Receptor Interactionsp. 82
The Role of Transmembrane Domainsp. 82
Protein Kinase Domain Structure and Functionp. 83
Catalytic Activity of Protein Kinasesp. 87
Steady State Kineticsp. 87
Chemistry of Protein Kinase Catalysisp. 89
Protein Kinase Regulationp. 91
Regulation Via Activation Segment Phosphorylationp. 92
Regulation by N-Terminal Sequences and Domainsp. 96
C-Terminal Regulatory Regionsp. 98
Regulation by Other Domains and Partner Proteinsp. 102
Referencesp. 107
Receptor Tyrosine Kinasesp. 119
EGF/ERBB Receptorsp. 120
ERBB Receptors and Cancerp. 128
Insulin/IGF Receptorsp. 130
Insulin/IGF Receptors and Cancerp. 134
Anaplastic Lymphoma Kinasep. 136
ALK and Cancerp. 137
VEGF Receptors (VEGFR1, VEGFR2, VEGFR3)p. 140
PDGF Receptorsp. 146
PDGFRs and Cancerp. 149
FGF Receptorsp. 153
FGFRs and Cancerp. 156
KITp. 158
KIT and Cancerp. 160
FLTp. 3165
FLT3 and Cancerp. 167
RETp. 168
RET and Thyroid Carcinomap. 169
MET and RONp. 170
METp. 170
RONp. 175
Referencesp. 177
Nonreceptor Tyrosine Kinasesp. 215
ABLp. 216
ARGp. 223
SRC and SRC Family Kinasesp. 224
SRCp. 228
Cellular Roles of SRCp. 232
SRC and Cancerp. 234
FAKp. 235
FAK and Cancerp. 238
JAKp. 238
Activation and Known Mutations and Fusions of the JAK Family of Tyrosine Kinasesp. 241
Further Roles of JAK2 in Tumor Growthp. 243
Referencesp. 246
Intracellular Signal Transduction Cascadesp. 265
The PI3K/PTEN Pathwayp. 266
PI3Kp. 267
PDK1p. 270
AKTp. 271
Other AGC Kinasesp. 273
PI3K Pathway Activation in Cancerp. 275
mTOR Signalingp. 279
mTORp. 279
p70S6 Kinasep. 282
mTOR Pathway Activation in Cancerp. 283
MAPK Signaling Pathwaysp. 284
ERK/MAPK Signalingp. 285
RAF Family Kinasesp. 286
MEK and ERK Kinasesp. 289
ERK/MAPK Pathway Activation in Cancerp. 291
PIM Kinasesp. 293
Protein Kinase Cp. 294
PKC Activationp. 295
Classical PKCsp. 298
Novel PKCsp. 299
Atypical PKCsp. 300
Referencep. 301
Cell Cycle Controlp. 327
Cyclin-Dependent Kinases (CDKs) and Cell Cycle Progressionp. 327
Introductionp. 328
CDK4 and CDK6p. 332
CDK2p. 334
CDK3p. 337
CDK1p. 337
CDK10p. 341
CCRK/CDCH/p42p. 341
CDKs and mRNA Productionp. 342
Introductionp. 342
CDK7p. 344
CDK8p. 346
CDK9p. 347
CDK11p. 348
CDK12 (CDC2-Related Kinase CRKRS)p. 350
CDK13 (CDC2L5)p. 351
Other CDK-Related Kinasesp. 352
CDK5p. 352
GAKp. 353
Mitotic Kinasesp. 354
PLKsp. 356
Aurora Kinasesp. 359
Cell Cycle Checkpoint Kinasesp. 361
ATM, ATR, and DNAPKp. 362
CHK1, CHK2, and MAPKAPK2p. 364
Referencesp. 364
Structural Biochemistry of Kinase Inhibitorsp. 391
Strategies for Inhibitor Designp. 392
Targeting the Active Versus Inactive Formp. 392
ATP-Competitive Versus Noncompetitive Inhibitorsp. 393
Specific Versus Multitargeted Inhibitorsp. 394
Architecture of the ATP Binding Site: DFG-inp. 396
Case Study: Inhibitors of CHK1p. 399
Case Study: Inhibitors of CDK2p. 407
Case Study: Inhibitors of SRC Family Kinasesp. 413
Case Study: EGF Receptor Inhibitorsp. 416
Targeting the Inactive Conformationp. 420
Binding Mode of Imatinibp. 421
Binding of BAY-43-9006 (Sorafenib) to the Inactive BRAF Kinasep. 423
Noncompetitive Inhibitionp. 424
Kinase Inhibitor Specificityp. 426
Referencesp. 429
Tyrosine Kinase Inhibitorsp. 435
BCR-ABL Inhibitorsp. 435
SRC Inhibitorsp. 446
JAK2 Inhibitorsp. 443
EGFR/ERBB Inhibitorsp. 452
Determinants of Response and Resistance to ERBB Inhibitorsp. 455
IGF1R Inhibitorsp. 470
FLT3 Inhibitorsp. 472
KIT Inhibitorsp. 480
MET/RON Inhibitorsp. 490
RET Inhibitorsp. 496
Other Inhibitorsp. 498
FAKp. 498
TGF Receptorp. 499
Referencesp. 500
Angiokinase Inhibitorsp. 527
Introductionp. 527
Angiokinase Inhibitorsp. 530
Referencesp. 555
Intracellular Signaling Kinase Inhibitorsp. 567
mTOR Inhibitorsp. 567
Clinical Pharmacodynamics and Tolerability of mTOR Inhibitorsp. 569
PI3K Inhibitorsp. 578
RAF Kinase Inhibitorsp. 582
MEK Inhibitorsp. 584
CDK Inhibitorsp. 587
Cell Cycle Checkpoint Kinase Inhibitorsp. 593
Mitotic Kinase Inhibitorsp. 597
PLK Inhibitorsp. 597
Aurora Kinase Inhibitorsp. 599
Protein Kinase C Inhibitorsp. 604
Referencesp. 605
Current Challenges and Future Directionsp. 623
Kinase Inhibitor Drug Resistancep. 623
Efflux Pumps and Drug Transportersp. 626
Other DMPK Factorsp. 627
Target Mutationp. 628
Target Overexpression and Activationp. 631
Downstream Pathway Activationp. 632
Redundant Receptors/Pathwaysp. 633
Combination Therapy With Kinase Inhibitorsp. 635
Angiogenesis Inhibitors and Chemotherapyp. 637
Survival Pathway Inhibitors and Chemotherapy/Targeted Therapyp. 638
DNA Damage Checkpoint Inhibitors and Chemotherapyp. 639
RTK Switching: Targeting Receptor Redundancyp. 640
Systems Biology and Translational Medicinep. 641
Classification of Tumors and Prediction of Response: Expression Profilingp. 642
Phosphoprotein Analysis, Kinomics, and Systems-Based Approachesp. 645
Translational Medicinep. 647
Conclusionsp. 652
Referencesp. 653
List of Abbreviationsp. 665
Indexp. 689
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